Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to novel compounds and compositions, and their use in the treatment of hyperglycaemia and disorders characterised by hyperglycaemia, such as type 2 diabetes.
• the invention relates to novel compounds, compositions and methods for the treatment of conditions such as type 2 diabetes through activation of the ⁇ 2 -adrenergic receptor.
• such compounds are thought to have a beneficial side-effect profile as they do not exert their effect through significant cAMP release.
• Hyperglycaemia or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. If not treated, hyperglycaemia can be a serious problem, potentially developing into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia may cause injury to the heart, and is strongly associated with heart attacks and death in subjects with no coronary heart disease or history of heart failure. There are various causes of hyperglycaemia, including diabetes and severe insulin resistance.
• Severe insulin resistance is a condition wherein the patent experiences very low levels of (or, in extreme cases, no significant) response to insulin.
• SIR Severe insulin resistance
• the majority of these conditions have genetic causes, such as mutations in the insulin receptor gene.
• the prevalence for Donohue's syndrome, Rabson-Mendenhall syndrome and Type A syndrome of insulin resistance has been reported to vary from about 50 reported cases to 1 in 100,000. However, since some diseases are severe and extremely rare, it is likely that many patients do not get diagnosed before they die, particularly in less developed areas of the world. Thus, the exact number of patients with these syndromes is difficult to assess.
• the current standard for hyperglycaemia treatment in patients having SIR is a controlled diet, supplemented with drugs affecting insulin receptor sensitivity, such as metformin, or insulin supplement.
• drugs affecting insulin receptor sensitivity such as metformin, or insulin supplement.
• this treatment is not sufficiently effective and ultimately proves unsuccessful.
• Type 2 diabetes affects more than 400 million people in the world and the number is rising rapidly. Complications of type 2 diabetes include severe cardiovascular problems, kidney failure, peripheral neuropathy, blindness and, in the later stages of the disease, even loss of limbs and, ultimately death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is presently no definitive cure. Most treatments used today are focused on remedying dysfunctional insulin signalling or inhibiting glucose output from the liver but many of those treatments have several drawbacks and side effects. There is thus a great interest in identifying novel insulin-independent ways to treat type 2 diabetes.
• type 2 diabetes the insulin-signalling pathway is blunted in peripheral tissues such as adipose tissue and skeletal muscle.
• Methods for treating type 2 diabetes typically include lifestyle changes, as well as insulin injections or oral medications to regulate glucose homeostasis.
• People with type 2 diabetes in the later stages of the disease develop 'beta-cell failure' i.e. the inability of the pancreas to release insulin in response to high blood glucose levels.
• patients often require insulin injections in combination with oral medications to manage their diabetes.
• most common drugs have side effects including downregulation or desensitization of the insulin pathway and/or the promotion of lipid incorporation in adipose tissue, liver and skeletal muscle. There is thus a great interest in identifying novel ways to treat metabolic diseases including type 2 diabetes that do not include these side effects.
• IR insulin receptor
• IRS insulin receptor substrate
• PI3K phosphoinositide 3-kinase
• AS160 phosphatidylinositol (3,4,5)-triphosphate
• Akt activation is considered necessary for GLUT4 translocation.
• skeletal muscles constitute a major part of the body weight of mammals and have a vital role in the regulation of systemic glucose metabolism, being responsible for up to 85% of whole-body glucose disposal.
• Glucose uptake in skeletal muscles is regulated by several intra- and extracellular signals. Insulin is the most well studied mediator but others also exist.
• AMPK AMP activated kinase
• Blood glucose levels may be regulated by both insulin and catecholamines, but they are released in the body in response to different stimuli. Whereas insulin is released in response to the rise in blood sugar levels (e.g. after a meal), epinephrine and norepinephrine are released in response to various internal and external stimuli, such as exercise, emotions and stress, and also for maintaining tissue homeostasis. Insulin is an anabolic hormone that stimulates many processes involved in growth including glucose uptake, glycogen and triglyceride formation, whereas catecholamines are mainly catabolic.
• insulin also stimulates many anabolic processes, including some that promote undesired effects such as stimulation of lipid incorporation into tissues, leading to e.g. obesity, it would be beneficial to be able to stimulate glucose uptake by other means; for example, by stimulation of the adrenergic receptors (ARs).
• ARs adrenergic receptors
• All ARs are G protein-coupled receptors (GPCRs) located in the cell membrane and characterized by an extracellular N-terminus, followed by seven transmembrane ⁇ -helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus.
• GPCRs G protein-coupled receptors
• TM-1 to TM-7 seven transmembrane ⁇ -helices
• IL-1 to IL-3 three intracellular loops
• EL-1 to EL-3 extracellular C-terminus.
• the ⁇ 1 -ARs comprise the ⁇ 1A , ⁇ 1B and ⁇ 1D subtypes while ⁇ 2 -ARs are divided into ⁇ 2A , ⁇ 2B and ⁇ 2C .
• the ⁇ -ARs are also divided into the subtypes ⁇ 1 , ⁇ 2 , and ⁇ 3 , of which ⁇ 2 -AR is the major isoform in skeletal muscle cells.
• ARs are G protein coupled receptors (GPCRs) that signal through classical secondary messengers such as cyclic adenosine monophosphate (cAMP) and phospholipase C (PLC).
• GPCRs G protein coupled receptors
• cAMP cyclic adenosine monophosphate
• PLC phospholipase C
• Glucose uptake is mainly stimulated via facilitative glucose transporters (GLUT) that mediate glucose uptake into most cells.
• GLUTs are transporter proteins that mediate transport of glucose and/or fructose over the plasma membrane down the concentration gradient.
• GLUT1-14 There are fourteen known members of the GLUT family, named GLUT1-14, divided into three classes (Class I, Class II and Class III) dependent on their substrate specificity and tissue expression.
• GLUT1 and GLUT4 are the most intensively studied isoforms and, together with GLUT2 and GLUT3, belong to Class I which mainly transports glucose (in contrast to Class II that also transports fructose).
• GLUT1 is ubiquitously expressed and is responsible for basal glucose transport.
• GLUT4 is only expressed in peripheral tissues such as skeletal muscle, cardiac muscle and adipose tissues. GLUT4 has also been reported to be expressed in, for example, the brain, kidney, and liver. GLUT4 is the major isoform involved in insulin stimulated glucose uptake. The mechanism whereby insulin signalling increases glucose uptake is mainly via GLUT4 translocation from intracellular storage to the plasma membrane. It is known that GLUT4 translocation is induced by stimulation of the ⁇ 2 -adrenergic receptor.
• a possible treatment of a condition involving dysregulation of glucose homeostasis or glucose uptake in a mammal, such as type 2 diabetes would involve the activation of the ⁇ 2 -adrenergic receptor leading to GLUT4 translocation to the plasma membrane and promotion of glucose uptake into skeletal muscle leading to normalization of whole body glucose homeostasis.
• the treatment does not involve signalling through cAMP as this would lead to a favourable side-effect profile.
• vasodilator 4-(2-(butylamino)-1-hydroxyethyl)phenol which has been used in the treatment of peripheral vascular disorders, has been found to initially increase blood sugar and has been contraindicated in diabetes and pre-diabetes (see Unger, H., Zeitschrift für die Automate Innere Medizin und Image Grenz whiche, 16, 742 (1961 )).
• US 3985887 describes 3-substituted-4-hydroxyphenyl-2-piperidylcarbinols as ⁇ -adrenergic stimulants.
• WO 2007/102011 describes compounds that may be used for the treatment or prevention of a condition associated with T-cell proliferation or that is mediated by pro-inflammatory cytokines.
• references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, e.g. compounds of formula IF) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments.
• salts include acid addition salts and base addition salts.
• Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
• carboxylate salts e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, ⁇ -hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or
• carboxylate salts e.
• sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts
• base addition salts include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
• Particular pharmaceutically acceptable salts that may be mentioned include acetate salts.
• compounds of the first aspect of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the first aspect of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. Compounds of the first aspect of the invention may also exist in solution.
• Compounds of the first aspect of the invention may contain double bonds and may thus exist as E ( Chrysler ) and Z ( 1966 ) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
• Compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
• Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
• the various stereoisomers i.e. enantiomers
• the desired optical isomers may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
• a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution); for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
• heterocycloalkyl may refer to non-aromatic, saturated and monocyclic groups wherein at least one atom comprised in the ring is a heteroatom (i.e. saturated heterocyclic groups).
• such groups may comprise from 1 to 4 heteroatoms, such as heteroatoms selected from O, S and N, which N may be present in secondary or tertiary degrees of substitution.
• references to halo and/or halogen groups will each independently refer to fluoro, chloro, bromo and iodo (for example, fluoro (F) and chloro (CI), such as F).
• C 1-z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C 3-z -cycloalkyl group).
• a sufficient number i.e. a minimum of four
• Part cyclic alkyl groups that may be mentioned include cyclopropylmethyl and cyclohexylethyl.
• such groups may also be multicyclic (e.g.
• alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2-z alkenyl or a C 2-z alkynyl group).
• Particular alkyl groups that may be mentioned include saturated alkyl groups.
• heteroatoms will take their normal meaning as understood by one skilled in the art.
• Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulphur (e.g. oxygen, nitrogen and sulphur).
• references to polycyclic (e.g. bicyclic or tricyclic) groups e.g. when employed in the context of cycloalkyl groups
• references to polycyclic (e.g. bicyclic or tricyclic) groups will refer to ring systems wherein at least two scissions would be required to convert such rings into a straight chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain).
• bicyclic e.g.
• alkyl groups when employed in the context of alkyl groups may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, and may also refer to groups in which two non-adjacent atoms are linked by an alkylene group, which later groups may be referred to as bridged.
• the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
• the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
• compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.
• z represents 1 or 2.
• z represents 1.
• z represents 2.
• R 1 represents at least C 2 alkyl, e.g. C 2-6 alkyl, such as C 2-3 alkyl.
• R 1 groups that may be mentioned include those in which the alkyl group is linear or part-cyclic (particularly, wherein the group is part-cyclic, such that the carbon bound to the ring containing the essential N atom is unbranched, e.g. -CH 2 - moiety).
• R 1 groups that may be mentioned include those in which the alkyl group is linear (e.g. ethyl, n -propyl, n -butyl, n -pentyl or n -hexyl).
• R 1 represents ethyl, n -propyl, isopropyl, n -butyl, sec- butyl, tert- butyl, 2-pentyl, cyclopentyl, -CH 2 -cyclopropyl, n -hexyl or cyclohexyl.
• R 1 represents ethyl or n-propyl.
• R 1 represents C 2-6 alkyl.
• R 1 represents C 2-6 alkyl, such as C 2-3 alkyl.
• R 1 represents C 2-6 alkyl (e.g. C 2-3 alkyl), particularly wherein the carbon bound to the ring containing the essential N atom is unbranched, e.g. represented by a -CH 2 - moiety.
• R 1 groups that may be mentioned include those in which the alkyl group (for example, a C 2-6 alkyl group) is linear or part-cyclic (particularly, wherein the group is part-cyclic, such that the carbon bound to the ring containing the essential N atom is unbranched, e.g. -CH 2 - moiety).
• R 1 groups that may be mentioned include those in which the alkyl group (e.g. the C 2-6 alkyl) is linear (e.g. ethyl, n -propyl, n -butyl, n -pentyl or n -hexyl).
• R 1 represents ethyl, n -propyl, isopropyl, n -butyl, sec- butyl, tert- butyl, 2-pentyl, cyclopentyl, -CH 2 -cyclopropyl, n -hexyl or cyclohexyl.
• R 1 represents n -propyl
• R 1 does not represent tert-butyl.
• n - indicates a linear alkyl group where the point of attachment of the group to the rest of a molecule is through a carbon atom at the end of the carbon chain and thus that that carbon atom is bound to one other carbon atom.
• secondary indicates that the point of attachment of the rest of the molecule to the alkyl group is through a carbon atom adjacent to the end of the carbon chain and thus that that carbon is itself bound to two other carbon atoms.
• tertiary indicates that the point of attachment of the alkyl group to the rest of a molecule is through a carbon atom that is bound to three other carbon atoms.
• R 1 represents C 2-3 alkyl and may be located in:
• each X independently represents F, CI, R a , -NH 2 or -OH, wherein R a represents C 1-2 alkyl optionally substituted by one or more F (for example R a represents -CH 3 , -CHF 2 or -CF 3 (e.g. -CF 3 )).
• each X independently represents F, CI, R a , or -OH, wherein R a represents C 1-2 alkyl optionally substituted by one or more F (e.g. -CF 3 ).
• each X independently represents F, Cl, -NH 2 , -CF 3 or -OH. In a further embodiment, each X independently represents -OH.
• each X independently represents Cl or F (e.g. where n represents 0, 1 or 2, such as 1). In a further embodiment, each X independently represents F (e.g. where n represents 0, 1 or 2, such as 1).
• n 2 to 4, such as where n represents 2)
• only one X group may represent -OH.
• n 0, 1, 2 or 3 (for example 1 or 2, e.g. 1).
• n 0, 1 or 2 (e.g. 0 or 1).
• n 1, 2 or 3 (e.g. 1 or 2).
• n 0 or 1 (e.g. 1).
• each X independently represents For CI, such as F, -NH 2 , -CF 3 or -OH. In further certain embodiments, wherein n represents 3, each X independently represents F, -NH 2 or -OH. In such embodiments, the X groups may be located in the 3-, 4- and 5-positions of the essential benzene ring.
• each X independently represents F, Cl, -NH 2 , or -OH.
• the X groups may be located in the 3- and 4-positions, or the 3- and 5- positions of the essential benzene ring.
• each X independently represents For -OH.
• the X groups may be located in the 3- and 4-positions, or the 3- and 5- positions of the essential benzene ring.
• X represents CI, F or -OH (e.g. Cl or F, such as F).
• the X group may be located in 3-position of the essential benzene ring.
• a compound of formula IF or a pharmaceutically acceptable salt thereof, wherein the essential benzene ring is unsubstituted in the 2- and 6-positions.
• X represents F, CI, R a or -OH
• R a represents C 1-2 alkyl optionally substituted by one or more F (for example, R a may represent -CH 3 , -CF 3 or -CHF 2 (e.g. -CHF 2 )) and n represents 1.
• X represents F or -OH (e.g. -OH) and n represents 1.
• X represents F or -OH (e.g. -OH) and n represents 1.
• X substituents are in the 3- and 4-position on the phenyl group to which they are attached.
• X represents F or -OH (e.g. -OH) in the 3-position on the phenyl group to which it is attached; and n represents 1.
• X represents CI, F or -OH (e.g. F) in the 3-position on the phenyl group to which it is attached; and n represents 1.
• More examples of more particular embodiments include those wherein: X represents Cl or F in the 2-position on the phenyl group to which it is attached; and n represents 1.
• X represents F or -OH (e.g. -OH) in the 4-position on the phenyl group to which it is attached; and n represents 1.
• At least one X is present (i.e. n represents at least 1) and represents other than -OH.
• At least one X is present and represents F.
• compounds of the first aspect of the invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Moreover, it has been found that certain such optical and/or diastereoisomers may show increased utility in the treatment of hyperglycaemia or disorders characterized by hyperglycaemia (such as type 2 diabetes), as described herein.
• the carbon substituted with the essential -OH group is in the (R) configuration.
• the compound of formula IF may be a compound of formula IH wherein z, X 1 , X 2 , X 3 , X 4 , X 5 , R 1 and R 2 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).
• the compound of formula IF is a compound of formula IH.
• stereochemistry at all stereocentres may be in either configuration (i.e. in the R or S configuration), or may be present in compounds as a mixture thereof (e.g. a racemic mixture).
• the compound of formula IH is a compound of formula IK or a compound of formula IL wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 and z are as defined in herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).
• the compound of formula IK is a compound of formula IM or a compound of formula IN
• the compound of formula IL is a compound of formula IO or a compound of formula IP wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 and z are as defined herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).
• Particular compounds of the first aspect of the invention include the compounds of the examples provided herein, and pharmaceutically acceptable salts thereof.
• references to specific stereoisomer(s) of a compound as represented by compounds of formulae IF, IH, IK, IL, IM, IN, IO, IP will refer to the specific stereoisomer present in the substantial absence of the other (corresponding) stereoisomer(s) (e.g. in the case of compounds of formula IF, where the carbon substituted by the essential -OH group is in the opposite configuration, i.e. the S configuration).
• references to a compound of formula IH will refer to that compound being present being present in the substantial absence of the corresponding opposite steroisomer (i.e a compound of formula IJ).
• references to the substantial absence of the corresponding opposite stereoisomer will refer to the desired stereoisomer (e.g. in the case of compounds of formula IF, where the carbon substituted by the essential -OH group is in the (R) configuration) being present at a purity of at least 90% (e.g. at least 95%) relative to the opposite stereoisomer (e.g. in the case of compounds of formula IF, where the carbon substituted by the essential -OH group is in the S configuration).
• compounds may be indicated to be present in the substantial absence of the compound in the other configuration (i.e.
• (S) configuration which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (e.e.), or when two or more stereogenic centres are defined, in a diastereomeric excess (d.e.), of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).
• compounds of the invention will include compounds wherein that position has either available sterochemical configuration, and mixtures (e.g. racemic mixtures) thereof.
• compounds referred to as having a specific stereochemistry at a defined position may also have stereochemistry at one or more other positions, and so may exist as mixtures of enantiomers or diastereoisomers in relation to the stereochemistry at those positions.
• references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).
• compositions and kits comprising the same are useful as pharmaceuticals.
• a compound of the first aspect of the invention as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in medicine).
• references to compounds as defined in the first aspect of the invention will include references to compounds of formula IF (including all embodiments thereof) and pharmaceutically acceptable salts thereof.
• the compounds of the invention may be of particular use in treating hyperglycaemia or a disorder characterized by hyperglycaemia.
• a compound of the first aspect of the invention for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.
• a method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IF, or a pharmaceutically acceptable salt thereof.
• hypoglycaemia as used herein will be understood by those skilled in the art to refer to a condition wherein an excessive amount of glucose circulates in blood plasma of the subject experiencing the same.
• a subject e.g a human subject
• blood glucose levels higher than about 10.0 mmol/L such as higher than about 11.1 mmol/L, e.g. higher than about 15 mmol/L
• a subject e.g a human subject
• blood glucose levels higher than about 7 mmol/L for an extended period of time e.g. for greater than 24 hours, such as for greater than 48 hours.
• references to the treatment of a particular condition take their normal meanings in the field of medicine.
• the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
• the term may refer to achieving a reduction of blood glucose levels.
• the term in the case of treating hyperglycaemia or conditions characterised by hyperglycaemia, the term may refer to achieving a reduction of blood glucose levels (for example, to or below about 10.0 mmol/mL (e.g.
• levels in the range of from about 4.0 mmol/L to about 10.0 mmol/L such as to or below about 7.5 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 7.5 mmol/L) or to or below about 6 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 6.0 mmol/L)).
• references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
• the treatment is in a mammal (e.g. a human).
• the term therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient.
• the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
• the compounds of the first aspect of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity.
• compounds of the first aspect of the invention are useful in the treatment of hyperglycaemia or disorders characterized by hyperglycaemia (such as type 2 diabetes), which terms will be readily understood by one of skill in the art (as described herein).
• the treatment is of a disorder (which may also be referred to as a condition or disease) characterised by hyperglycaemia.
• compounds of the invention are for use in the treatment of type 2 diabetes (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).
• the disorder is type 2 diabetes, such as type 2 diabetes of a sub-type selected from the list consisting of maturity-onset diabetes in the young (MODY), ketosis-prone diabetes in adults, latent autoimmune diabetes of adults (LADA), and gestational diabetes.
• type 2 diabetes such as type 2 diabetes of a sub-type selected from the list consisting of maturity-onset diabetes in the young (MODY), ketosis-prone diabetes in adults, latent autoimmune diabetes of adults (LADA), and gestational diabetes.
• the treatment of type 2 diabetes is in a non-obese patient.
• BMI Body Mass Index
• the treatment may be of hyperglycaemia in a patent who is at risk of developing type 2 diabetes, which condition may be defined as pre-diabetes.
• compounds of the invention may be useful in the prevention of type 2 diabetes (e.g. in a patient having pre-diabetes).
• prevention includes references to the prophylaxis of the disease or disorder (and vice-versa).
• references to prevention may also be references to prophylaxis, and vice versa.
• the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
• the type 2 diabetes is characterised by the patient displaying severe insulin resistance (SIR).
• SIR severe insulin resistance
• the treatment may be of hyperglycaemia in a patient having type 1 diabetes.
• compounds of the invention may be useful in the treatment of hyperglycaemia in type 1 diabetes.
• the disorder characterized by hyperglycaemia is cystic fibrosis-related diabetes.
• the disorder characterised by hyperglycaemia is (or is characterized by) severe insulin resistance (SIR), which may be understood by those in the art to refer to disorders wherein typically the subject has normal, or in some cases increased, insulin production but significantly reduced insulin sensitivity.
• SIR severe insulin resistance
• such patients may be non-obese (e.g. being of a healthy weight).
• such treatments are performed in patients who are not defined as being obese (e.g. in patients who are defined as being of a healthy weight).
• SIR may be identified in a patient based in said patient having fasting insulin >150 pmol/L and/or a peak insulin on glucose tolerance testing of >1,500 pmol/L, particularly in individuals with a BMI ⁇ 30kg/m 2 (which patient may otherwise have normal glucose tolerance).
• SIR may be characterised by the patient having no significant response to the presence of insulin, which may result from a defect (e.g. a genetic defect) in the function of the insulin receptor.
• a defect e.g. a genetic defect
• SIR SIR-Mendenhall syndrome
• Donohue's syndrome leprechaunism
• Type A and Type B syndromes of insulin resistance the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndromes
• pseudoacromegaly and lipodystrophy.
• SIR SIR More particular disorders that may be characterised by SIR include Donohue's syndrome and Type A syndrome of insulin resistance and, yet more particularly, Rabson-Mendenhall syndrome.
• treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with compounds of the invention may be combined with other means for the treatment of type 2 diabetes, such as treatment with one or more other therapeutic agent that is useful in the treatment of type 2 diabetes as known to those skilled in the art, such as therapies comprising requiring the patient to undergo a change of diet and/or undertake exercise regiments, and/or surgical procedures designed to promote weight loss (such as gastric band surgery).
• treatment with compounds of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that:
• compounds of the first aspect of the invention may be useful in the treatment of a non-alcoholic fatty liver disease (NAFLD).
• NAFLD non-alcoholic fatty liver disease
• Non-alcoholic fatty liver disease is defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver (designated as an accumulation of greater than 5% of hepatocytes histologically). It is the most common liver disorder in developed countries (for example, affecting around 30% of US adults) and most patients are asymptomatic. If left untreated, the condition may progressively worsen and may ultimately lead to cirrhosis of the liver. NAFLD is particularly prevalent in obese patents, with around 80% thought to have the disease.
• NASH non-alcoholic steatohepatitis
• NASH The exact cause of NASH has yet to be elucidated, and it is almost certainly not the same in every patient. It is most closely related to insulin resistance, obesity, and the metabolic syndrome (which includes diseases related to diabetes mellitus type 2, insulin resistance, central (truncal) obesity, hyperlipidaemia, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and hypertension).
• diabetes mellitus type 2 insulin resistance
• central (truncal) obesity hyperlipidaemia
• HDL low high-density lipoprotein
• hypertriglyceridemia hypertension
• compounds of the invention are for use in the treatment of a non-alcoholic fatty liver disease (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).
• steatosis i.e. hepatic steatosis
• the term "steatosis” encompasses the abnormal retention of fat (i.e. lipids) within a cell.
• the treatment or prevention is of a fatty liver disease which is characterized by steatosis.
• lipids During steatosis, excess lipids accumulate in vesicles that displace the cytoplasm of the cell. Over time, the vesicles can grow large enough to distort the nucleus, and the condition is known as macrovesicular steatosis. Otherwise, the condition may be referred to as microvesicular steatosis.
• Steatosis is largely harmless in mild cases; however, large accumulations of fat in the liver can cause significant health issues. Risk factors associated with steatosis include diabetes mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea and the presence of toxins within the cell.
• fatty liver disease is most commonly associated with alcohol or a metabolic syndrome (for example, diabetes, hypertension, obesity or dyslipidemia). Therefore, depending on the underlying cause, fatty liver disease may be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).
• NAFLD non-alcoholic fatty liver disease
• Particular diseases or conditions that are associated with fatty liver disease that are not related to alcohol include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, acute fatty liver of pregnancy, and lipodystrophy.
• Other non-alcohol related factors related to fatty liver diseases include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome and diverticulosis.
• the compounds of the invention have been found to be particularly useful in the treatment or prevention of NAFLD, which may be referred to as a fatty liver disease which is not alcohol related.
• a fatty liver disease which is "not alcohol related” may be diagnosed wherein alcohol consumption of the patient is not considered to be a main causative factor.
• a typical threshold for diagnosing a fatty liver disease as "not alcohol related" is a daily consumption of less than 20 g for female subjects and less than 30 g for male subjects.
• the treatment or prevention is of a NAFLD which is associated with inflammation.
• Non-alcoholic steatohepatitis is the most aggressive form of NAFLD, and is a condition in which excessive fat accumulation (steatosis) is accompanied by inflammation of the liver. If advanced, NASH can lead to the development of scar tissue in the liver (fibrosis) and, eventiually, cirrhosis.
• the compounds of the invention have been found to be useful in the treatment or prevention of NAFLD, particularly when accompanied by inflamation of the liver. It follows that the compounds of the invention are also useful in the treatment or prevention of NASH. Therefore, in a further embodiment of the first aspect of the invention, the treatment or prevention is of non-alcoholic steatohepatitis (NASH).
• treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with compounds of the invention may be combined with other means for the treatment of a fatty liver disease, as described herein, such as treatment with one or more other therapeutic agent that is useful in the treatment of a fatty liver disease as known to those skilled in the art; for example, therapies comprising requiring the patient to undergo a change of diet and/or undertake exercise regiments, and/or surgical procedures designed to promote weight loss (such as gastric band surgery).
• treatment with compounds of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that are capable of reducing the level of fat (e.g. triglycerides) in the liver.
• additional compounds i.e. therapeutic agents
• references to treatment of a fatty liver disease may refer to achieving a therapeutically significant reduction of fat (e.g. triglycerides levels) in liver cells (such as a reduction of at least 5% by weight, e.g. a reduction of at least 10%, or at least 20% or even 25%).
• fat e.g. triglycerides levels
• liver cells such as a reduction of at least 5% by weight, e.g. a reduction of at least 10%, or at least 20% or even 25%.
• compounds of the first and, therefore, the second and third aspects of the invention are useful as pharmaceuticals. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions/formulations.
• a pharmaceutical composition comprising a compound as defined in the second or third aspect of the invention, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.
• references herein to compounds of the first aspect of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention as described herein.
• a pharmaceutical composition for use in the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia comprising a compound as defined in the first aspect of the invention, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.
• a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease as defined herein.
• a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease as defined herein.
• compounds of the first (and, therefore, second and third) aspect of the invention may act systemically and/or locally (i.e. at a particular site).
• compositions as described in the first to fifth aspects of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
• Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, particularly where such compounds of the invention act locally, pharmaceutical compositions may be formulated for topical administration.
• the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration.
• a pharmaceutically acceptable dosage form including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration.
• compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.
• the compound in the preparation of pharmaceutical formulations for oral administration, may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
• the mixture may then be processed into granules or compressed into tablets.
• Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
• active compounds e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents
• hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
• Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
• Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
• Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
• Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
• compositions as described hereinabove may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art.
• Oral, pulmonary and topical dosages may range from between about 0.01 ⁇ g/kg of body weight per day ( ⁇ g/kg/day) to about 200 ⁇ g/kg/day, preferably about 0.01 to about 10 ⁇ g/kg/day, and more preferably about 0.1 to about 5.0 ⁇ g/kg/day.
• treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 ⁇ g to about 2000 mg, for example between about 0.1 ⁇ g to about 500 mg, or between 1 ⁇ g to about 100 mg (e.g. about 20 ⁇ g to about 80 mg), of the active ingredient(s).
• the most preferred doses will range from about 0.001 to about 10 ⁇ g/kg/hour during constant rate infusion.
• treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily, or 10 ⁇ g, 20 ⁇ g, 30 ⁇ g or 40 ⁇ g twice daily).
• the skilled person e.g. the physician
• the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
• treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with compounds of the invention may be combined with other means for the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia(as defined herein, such as type 2 diabetes), such as treatment with one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia(as defined herein, such as type 2 diabetes).
• the pharmaceutical composition may further comprise one or more additional (i.e. other) therapeutic agent.
• the one or more additional therapeutic agent is an agent for the treatment of type 2 diabetes as known to those skilled in the art, such as metformin, sulfonylureas (e.g. carbutamide, acetohexamide, chlorpropamide, tolbutamide. glipizide (glucotrol), gliclazide, glibenclamide, glyburide (Micronase), glibornuride, gliquidone, glisoxepide, glyclopyramide, glimepiride (Amaryl), glimiprime, JB253 or JB558), thiazolidinediones (e.g.
• metformin e.g. carbutamide, acetohexamide, chlorpropamide, tolbutamide.
• glipizide glucotrol
• gliclazide glibenclamide
• glyburide Micronase
• glibornuride gliquidone
• dipeptidyl peptidase-4 inhibitors e.g. sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin and omarigliptin
• SGLT2 inhibitors e.g.
• dapagliflozin empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, and ertugliflozin), and glucagon-like peptide-1 (GLP-1) analogues.
• GLP-1 glucagon-like peptide-1
• a combination product comprising:
• kit-of-parts comprising:
• the additional therapeutic agent is a therapeutic agent that is useful for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), as known to those skilled in the art (such as those described herein).
• hyperglycaemia e.g. type 2 diabetes
• the additional therapeutic agent is an agent that:
• references to therapeutic agents capable of reducing blood glucose levels may refer to compounds capable of reducing levels of blood by at least 10% (such as at least 20%, at least 30% or at least 40%, for example at least 50%, at least 60%, at least 70% or at least 80%, e.g. at least 90%) when compared to the blood glucose levels prior to treatment with the relevant compound.
• the additional therapeutic agent is an agent for the treatment or prevention of a non-alcoholic fatty liver disease (such as NASH), which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
• a non-alcoholic fatty liver disease such as NASH
• agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
• compositions/formulations, combination products and kits as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.
• a process for the preparation of a pharmaceutical composition/formulation comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable adjuvant, diluent or carrier.
• a process for the preparation of a combination product or kit-of-parts as hereinbefore defined comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
• references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
• kits of parts as hereinbefore defined, by bringing the two components "into association with” each other, we include that the two components of the kit of parts may be:
• the substituents X and R 1 may be modified one or more times, after or during the processes described above for preparation of compounds of formula I by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations.
• the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
• the skilled person may also refer to " Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and/or " Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999 .
• processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention (e.g. isolation and optionally purification of the compound of formula IF).
• Protecting groups may be applied and removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in " Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999 ).
• Compounds as described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
• such compounds may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
• compounds as described herein are thought to be potent agonists of the ⁇ 2 -adrenergic receptor, which allows for increased glucose uptake in skeletal muscle cells.
• compounds as described herein are thought to be agonists of the ⁇ 2 -adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. It is thought that this allows for the increased glucose uptake in skeletal muscle cells with lower levels of side effects than would result from other treatments. Further, combining compounds as described herein with therapeutic agents that are able to decrease blood glucose levels is thought to provide an effective combination therapy.
• Fluorophenylmagnesium bromide (0.94 mmol in THF, prepared from 1-bromo-3-fluorobenzene and Mg) was added to a solution of tert -butyl (2 R ,6 R )-2-formyl-6-propylpiperidine-1-carboxylate (0.20 mg, 0.78 mmol) in THF (5 mL) at -20 °C. The mixture was stirred at -20 °C for 20 min and NH 4 Cl (aq, sat, 5 mL) was added. The mixture was extracted with EtOAc and the combined extracts dried over Na 2 SO 4 , concentrated and purified by chromatography to give the sub-title compound (146 mg, 0.42 mmol, 53 %).
• the sub-title compound was prepared in accordance with the procedure in Example 1, Step (a) from ( S )-(+)-coniine hydrochloride.
• the sub-title compound was prepared in accordance with the procedure in Example 2, Step (b), using 3-benzyloxybenzaldehyde.
• Benzyl chloroformate (0.85 mL, 5.9 mmol) was added during 20 min to a solution of methyl (R)-5-oxopyrrolidine-2-carboxylate (500 mg, 3.5 mmol), DMAP (0.19 g, 1.6 mmol) and DIPEA (0.82 ml) in MeCN (7 mL) at rt. After 2 h additional portions of DMAP (0.19 g, 1.6 mmol), DIPEA (0.82 ml) and benzyl chloroformate (0.85 mL, 5.9 mmol) were added and stirring was continued for another 3 h. The mixture was concentrated and EtOAc was added to the residue. The mixture was washed with brine, dried over Na 2 SO 4 , concentrated and purified by chromatography to give the sub-title compound (775 mg, 2.8 mmol, 80 %).
• Example 9 Racemic mixture of 3-((R)-Hydroxy((2S,5S)-5-methylpyrrolidin-2-yl)methyl)-phenol acetate and 3-((S)-Hydroxy((2R,5R)-5-methylpyrrolidin-2-yl)methyl)phenol acetate (Reference example)
• Triethylamine (2.6 mL, 18.9 mmol) was added to a solution of tert-butyl 2-bromo-3-tosyl-7-azabicyclo[2.2.1]hepta-2,5-diene-7-carboxylate (1.61 g, 3.8 mmol) in MeCN (50 mL) at rt. Diethylamine (0.47 mL, 4.5 mmol) was slowly added and the mixture was stirred at rt for 2 h. HCl (4 M, 16 mL) was added and the mixture was stirred at rt for 3 h. CH 2 Cl 2 (140 mL) was added and the mixture was washed with H 2 O. The aq phase was extracted with CH 2 Cl 2 and the combined organic phases were dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography to give the sub-title compound (0,98 g, 2.7 mmol, 72 %).
• Example 10 Racemic mixture of 3-((R)-Hydroxy((2R,5R)-5-methylpyrrolidin-2-yl)methyl)-phenol acetate and 3-((S)-Hydroxy((2S,5S)-5-methylpyrrolidin-2-yl)methyl)phenol acetate (Reference example)
• Example 11 Racemic mixture of (R)-((2S,5S)-5-Methylpyrrolidin-2-yl)(phenyl)methanol and (S)-((2R,5R)-5-Methylpyrrolidin-2-yl)(phenyl)methanol (Reference example)
• Example 12 Racemic mixture of (R)-((2R,5R)-5-Methylpyrrolidin-2-yl)(phenyl)methanol and (S)-((2S,5S)-5-Methylpyrrolidin-2-yl)(phenyl)methanol (Reference example)
• the title compound was obtained from 3-fluorophenylmagnesium bromide and tert-butyl (2 R ,6 R )-2-formyl-6-propylpiperidine-1-carboxylate, first by isolating the intermediate tert- butyl (2 R ,6 R )-2-(( S )-(3-fluorophenyl)(hydroxy)methyl)-6-propylpiperidine-1-carboxylate in the chromatographic purification step described in Example 1, Step (c) followed by the removal of the protecting group as described in Example 1, Step (d).
• the title compound was obtained from tert-butyl (S)-2-propylpiperidine-1-carboxylate and 3-fluorobenzaldehyde as described in Example 2 by first by isolating the intermediate tert-butyl (2R,6S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-6-propylpiperidine-1-carboxylate in the chromatographic purification step described in Example 2, Step (b) followed by the removal of the protecting group as decribed in Example 2, Step (c).
• the title compound was prepared from tert -butyl ( R )-2-propylpiperidine-1-carboxylate and 3-benzyloxybenzaldehyde in accordance with the procedure in Example 2, Step (d), followed by the removal of the protecting groups as decribed in Example 2, Step (c) and Example 5, Step (c), but using iPrOH as a solvent in the last step.
• the hydrochloride salt was obtained by dissolution of the free base in Et 2 O followed by precipitation by addition of HCl (2 M in Et 2 O).
• the benzyloxy group was then removed by adding Pd-C (10%, 52 mg, 0.049 mmol) and triethylsilane (390 ⁇ L, 2.44 mmol) to a solution of the intermediate (S)-(3-(benzyloxy)-phenyl)((2R,6R)-6-propylpiperidin-2-yl)methanol (83 mg, 0.24 mmol) in MeOH (4 mL). The mixture was stirred at rt for 10min, filtered through Celite and concentrated. The residue was dissolved in MeOH (1 mL), filtered through Celite and concentrated.
• Example 36 (R)-(3-Chlorophenyl)((2S,6S)-6-propylpiperidin
• Lithium triethyl borohydride (1.7M in THF, 1.27 mL, 2.16 mmol) was added to a stirred solution of 1-benzyl 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (500 mg, 1.80 mmol) in THF (14 mL) at -78 °C. The mixture was stirred for 30 min at -78 °C. NaHCOs (aq, sat) was added and the temperature was allowed to reach rt. EtOAc was added and the aq phase extracted with EtAOc. The combined organic phases were washed with brine, dried (Na 2 SO 4 ) and concentrated to give the sub-title product (496 mg, 99%), which was used in the next step without further purification.
• nPrMgCl (1M in THF, 8.59 mL, 8.59 mmol) was added dropwise to a stirred mixture of CuBr ⁇ SMe 2 (1.77 g, 8.59 mmol) in THF (16 mL) at -40 °C. After 45 min at -40 °C, the mixture was cooled to -78 °C. BF 3 ⁇ OEt 2 (1.08 mL, 8.59 mmol) was added dropwise, followed after 30 min stirring at -78 °C by a solution of 1-benzyl 2-methyl ( 2S )-5-methoxy-pyrrolidine-1,2-dicarboxylate (557 mg, 1.90 mmol) in THF (3 mL).
• N,O-dimethylhydroxylamine hydrochloride (445 mg, 1.45 mmol) was added followed by dropwise addition of i PrMgCl (2M in THF, 1.45 mL, 2.91 mmol). The mixture was stirred for 10 min at -10 °C. NH 4 Cl (aq, sat, 4 mL) was added and the mixture extracted with EtOAc. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give the sub-title product (472 mg, 97%), which was used in the next step without further purification.
• the sub-title compound was prepared from benzyl (2S,5R)-2-(methoxy(methyl)-carbamoyl)-5-propylpyrrolidine-1-carboxylate and 3-fluorophenylmagnesium bromide in accordance with the procedure in Example 7, Step (f).
• the sub-title compound was prepared from benzyl (2S,5R)-2-(3-fluorobenzoyl)-5-propylpyrrolidine-1-carboxylate in accordance with the procedure in Example 41, Step (c).
• the sub-title compound was prepared from 1-(tert-butyl) 2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylate and 3-fluorophenylmagnesium bromide in accordance with the procedures in Example 43, Steps (a) to (f).
• the sub-title compound was prepared from 1-( tert -butyl) 2-methyl ( R )-5-oxopyrrolidine-1,2-dicarboxylate and 3-benzyloxyphenylmagnesium bromide in accordance with the procedures in Example 43, Steps (a) to (f).
• the sub-title compound was prepared from 1-( tert -butyl) 2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylate and n-propylmagnesium chloride in accordance with the procedure in Example 7, Step (b).
• the title compound was prepared in accordance with the procedures in Example 7, Steps (d) to (f) and Example 2, Step (c) from 1-( tert -butyl) 2-methyl ( 2R,5S )-5-propylpyrrolidine-1 ,2-dicarboxylate and 3-chlorophenyl magnesium bromide.
• the maleate salt was prepared by adding maleic acid (25 mg, 0.21 mmol) in EtOAc (0.8 mL) to a solution of the free base (42.7 mg, 0.18 mmol) in EtOAc (0.2 mL), concentration and reverse phase chromatography.
• L6- myoblasts were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 4,5 g/l glucose supplemented with 10% fetal bovine serum, 2 mM L-Glutamine, 50 U/ml penicillin, 50 ⁇ g/ml streptomycin and 10 mM HEPES. Cells were plated at 1 ⁇ 10 5 cells per ml in 24- well plates. After reaching 90 % confluence the cells were grown in medium containing 2% FBS for 7 days where upon cells differentited into myotubes.
• DMEM Dulbecco's Modified Eagle's Medium
• Differentiated L6- myotubes were serum-starved over night in medium containing 0,5 % fatty- acid free BSA and stimulated with agonist, final concentration 1 ⁇ 10 -5 . After 1 h 40 min cells were washed with warm, glucose free medium or PBS and another portion of agonist was added to glucose free medium. After 20 min the cells were exposed to 50 nM 3 H-2- deoxy- glucose for another 10 min before washed in ice cold glucose free medium or PBS and lysed in 0,2 M NaOH for 1 h in 60° C. Cell lysate was mixed with scintillation buffer (Emulsifier Safe, Perkin Elmer and radioactivity detected in a ⁇ -counter (Tri- Carb 2800TR, Perkin Elmer).
• scintillation buffer Emulsifier Safe, Perkin Elmer and radioactivity detected in a ⁇ -counter (Tri- Carb 2800TR, Perkin Elmer).
• the activity for each compound is compared to that of isoproterenol. If a compound shows activity of more than 75 % of that of isoproterenol, the activity is denoted with +++, if it is between 75 and 50 % it is denoted with ++; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -.
• Differentiated cells were serum-starved over night and stimulated with agonist, final concentration 1 ⁇ 10- 5 , for 15 min in stimulation buffer (HBSS supplemented with 1% BSA, 5 mM HEPES and 1 mM IBMX, pH 7,4)
• stimulation buffer HBSS supplemented with 1% BSA, 5 mM HEPES and 1 mM IBMX, pH 7,4
• the medium was then aspirated and to end the reaction 100 ⁇ L of 95 % EtOH was added to each well of a 24- well plate and cells were kept in -20° C over night.
• the EtOH was let to evaporate and 500 ⁇ L of lysis buffer (1 % BSA, 5 mM HEPES and 0,3 % Tween- 20, pH 7,4) was added to each well before put in -80° C for 30 min and then kept in -20° C.
• Intracellular cAMP levels were detected using an alpha screen cAMP kit (6760635D from Perkin Elmer). The activity for each compound is compared to that of isoproterenol. If a compound shows activity of more than 75 % of that of isoproterenol, the activity is denoted with +++, if it is between 75 and 50 % it is denoted with ++; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pyrrole Compounds (AREA)

Applications Claiming Priority (2)

Publications (3)

Family

ID=60117153

Family Applications (1)

Country Status (13)

Families Citing this family (11)

Citations (1)

Family Cites Families (137)

• 2017
  • 2017-09-13 GB GBGB1714740.6A patent/GB201714740D0/en not_active Ceased
• 2018
  • 2018-09-13 US US16/646,050 patent/US11427539B2/en active Active
  • 2018-09-13 WO PCT/GB2018/052593 patent/WO2019053425A1/en not_active Ceased
  • 2018-09-13 CN CN201880064177.4A patent/CN111164072A/zh active Pending
  • 2018-09-13 EP EP18773560.0A patent/EP3681862B1/en active Active
  • 2018-09-13 AU AU2018332145A patent/AU2018332145A1/en not_active Abandoned
  • 2018-09-13 JP JP2020514512A patent/JP7346388B2/ja active Active
  • 2018-09-13 KR KR1020207010468A patent/KR20200051776A/ko not_active Ceased
  • 2018-09-13 RU RU2020108488A patent/RU2020108488A/ru unknown
  • 2018-09-13 BR BR112020005064-4A patent/BR112020005064A2/pt not_active Application Discontinuation
  • 2018-09-13 MX MX2020002824A patent/MX2020002824A/es unknown
  • 2018-09-13 CA CA3075705A patent/CA3075705A1/en active Pending
• 2020
  • 2020-03-09 IL IL273171A patent/IL273171A/en unknown

Patent Citations (1)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events